Correction: Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.

[This corrects the article DOI: 10.1371/journal.pgen.

Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.

Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB).

Data Mining and Computational Modeling of High-Throughput Screening Datasets.

We are now seeing the benefit of investments made over the last decade in high-throughput screening (HTS) that is resulting in large structure activity datasets entering public and open databases such as ChEMBL and PubChem. The growth of academic HTS screening centers and the increasing move to academia for early stage drug discovery suggests a great need for the informatics tools and methods to mine such data and learn from it. Collaborative Drug Discovery, Inc.

Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease.

The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients.

Studying human disease using human neurons.

Utilizing patient derived cells has enormous promise for discovering new drugs for diseases of the nervous system, a goal that has been historically quite challenging. In this review, we will outline the potential of human stem cell derived neuron models for assessing therapeutics and high-throughput screening and compare to more traditional drug discovery strategies. We summarize recent successes of the approach and discuss special considerations for developing human stem cell based assays.

Thermodynamic Proxies to Compensate for Biases in Drug Discovery Methods.

Purpose: We propose a framework with simple proxies to dissect the relative energy contributions responsible for standard drug discovery binding activity.

Methods: We explore a rule of thumb using hydrogen-bond donors, hydrogen-bond acceptors and rotatable bonds as relative proxies for the thermodynamic terms. We apply this methodology to several datasets (e.

A brief review of recent Charcot-Marie-Tooth research and priorities.

This brief review of current research progress on Charcot-Marie-Tooth (CMT) disease is a summary of discussions initiated at the Hereditary Neuropathy Foundation (HNF) scientific advisory board meeting on November 7, 2014. It covers recent published and unpublished in vitro and in vivo research. We discuss recent promising preclinical work for CMT1A, the development of new biomarkers, the characterization of different animal models, and the analysis of the frequency of gene mutations in patients with CMT.

Collaboration for rare disease drug discovery research.

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases.

Databases and collaboration require standards for human stem cell research.

Stem cell research is at an important juncture: despite significant potential for human health and several countries with key initiatives to expedite commercialization, there are gaps in capturing and exploiting the results of past and current research. Here, we propose a concerted plan that could be taken to foster a more collaborative approach and ensure that all research efforts can be leveraged across the community. The creation of a definitive centralized database repository, or at least harmonized data repositories, for stem cell groups in academia and industry, enabling secure selective sharing of data when needed, could provide the core structure that is sought globally and protect intellectual property.

Parallel worlds of public and commercial bioactive chemistry data.

The availability of structures and linked bioactivity data in databases is powerfully enabling for drug discovery and chemical biology. However, we now review some confounding issues with the divergent expansions of public and commercial sources of chemical structures. These are associated with not only expanding patent extraction but also increasingly large vendor collections amassed via different selection criteria between SciFinder from Chemical Abstracts Service (CAS) and major public sources such as PubChem, ChemSpider, UniChem, and others.

Computational prediction and validation of an expert's evaluation of chemical probes.

In a decade with over half a billion dollars of investment, more than 300 chemical probes have been identified to have biological activity through NIH funded screening efforts. We have collected the evaluations of an experienced medicinal chemist on the likely chemistry quality of these probes based on a number of criteria including literature related to the probe and potential chemical reactivity. Over 20% of these probes were found to be undesirable.

Fast and accurate semantic annotation of bioassays exploiting a hybrid of machine learning and user confirmation.

Bioinformatics and computer aided drug design rely on the curation of a large number of protocols for biological assays that measure the ability of potential drugs to achieve a therapeutic effect. These assay protocols are generally published by scientists in the form of plain text, which needs to be more precisely annotated in order to be useful to software methods. We have developed a pragmatic approach to describing assays according to the semantic definitions of the BioAssay Ontology (BAO) project, using a hybrid of machine learning based on natural language processing, and a simplified user interface designed to help scientists curate their data with minimum effort.

Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors.

In the adult central nervous system, the vasculature of the neurogenic niche regulates neural stem cell behavior by providing circulating and secreted factors. Age-related decline of neurogenesis and cognitive function is associated with reduced blood flow and decreased numbers of neural stem cells. Therefore, restoring the functionality of the niche should counteract some of the negative effects of aging.

Peroxynitrite mediates active site tyrosine nitration in manganese superoxide dismutase. Evidence of a role for the carbonate radical anion.

Protein tyrosine nitration has been observed in a variety of human diseases associated with oxidative stress, such as inflammatory, neurodegenerative, and cardiovascular conditions. However, the pathways leading to nitration of tyrosine residues are still unclear. Recent studies have shown that peroxynitrite (PN), produced by the reaction of superoxide and nitric oxide, can lead to protein nitration and inactivation.

Expression and characterization of the isolated glycosyltransferase module of Escherichia coli PBP1b.

The enzymes involved in the biosynthesis of peptidoglycan are targets for the development of new antibiotics. The bifunctional high molecular weight (HMW) penicillin-binding proteins (PBPs), which contain both glycosyltransferase (GTase) and transpeptidase (TPase) activities, are particularly attractive targets because of their extracellular location. However, there is limited mechanistic or structural information about the GTase modules of these enzymes.